[unreadable] Proposed here is a supplemental application for the UTHHSC Specialized Center of Research (SCOR) in Scleroderma to expand the application of gene expression analyses in understanding the molecular pathogenesis of scleroderma or systemic sclerosis (SSe), especially genetics, which is the overall theme of the SCOR. SSc is a chronic, multisystem disease with high morbidity and mortality characterized by widespread skin and internal organ fibrosis, blood vessel damage, and a variety of circulating, highly disease specific auto antibodies to nuclear components. The fibrosis is caused by activation of fibroblasts that produce excessive amounts of collagen and other extra-cellular matrix (ECM) constituents. Although the etiology of SSc is unknown, it is believed to be a complex disorder of autoimmune origin, and this proposal aims to use gene expression profiles to explore the relationship between fibroblast activation/expression and SSc autoantibodies. Previously, SCOR investigators have discovered a genetic link between the fibrillin-1 gene (FBN1) and SSc susceptibility, as well as functional abnormalities in vitro of fibrillin-1 containing micro fibrils in cultured fibroblasts of SSc patients. In addition, highly disease-specific auto antibodies tofibrillin-1 have been detected in the sera of the majority of patients with SSc. Using eDNA microarrays and RT-PCR of SSc fibroblasts, our studies have revealed selectively increased expression of SSc-specific auto antigen genes, including to poisomerase I, CENP B, RNA polymerase II, fibrillarin, and PM-Scl.Moreover, preliminary studies using arrays suggest that anti-fibrillin-1 antibodies can activate normal fibroblasts and induce a gene expression profile similar to that of SSc, including auto antigen gene over expression. Therefore, the specific aims of this proposal are: 1) using microarrays to profile over 16,659genes, to determine a distinctive and predictable transcript profile in SSc fibroblasts (and clinical and auto antibody subsets thereof); 2) to stimulate normal dermal fibroblasts with affinity-purified anti-fibrillin-1antibodies to determine whether the SSc transcript profile identified above is recapitulated by these antibodies and identify important cellular and/or metabolic pathways involved; and 3) to stimulate normal dermal and lung fibroblasts with the SSc-specific nuclear auto antibodies to determine using arrays, whether these antibodies also can activate fibroblasts and/or have other effects on fibroblasts from various tissues, accounting for their associations with clinical features. These studies will provide important new information about pathogenic mechanisms in SSc and potentially lead to new therapeutic or preventative strategies. [unreadable] [unreadable] [unreadable]